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Gait Speed/Mitochondria/ Functional Decline in HIV+ - The Role of Mitochondrial DNA Variation in Age-Related Decline in Gait Speed Among Older Men Living with HIV
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"Gait speed is an independent measure of physical function and a component of the assessment of frailty, and has been shown to predict functional decline, hospitalization, disability and deaths among older adults[6, 9].
An accelerated rate of decline in gait speed has been noted in older PLWHIV, which could be attributed to multiple factors, including characteristics shared with the general population (reduced energy production[10], compromised energy consumption [10, 11], changes in body composition [12], etc.), as well as unique challenges from HIV chronic infection[13, 14].......mitochondrial function among PLWHIV could be damaged by HIV chronic infection [14] and long-term usage of ART [13], which trigger proinflammatory responses that could lead to impaired physical function. It is possiblethat mtDNA genetic variation interact with multiple mechanisms and confer additional susceptibility to certain individuals.........Among older, HIV-infected men, mtDNA haplogroup J was an independent risk factor for more rapid age-related gait speed decline.......Consistent with our previous study performed in MACS [6], HIV viral suppression did not have a significant effect on gait speed. However,having ever been diagnosed with AIDS, higher viremia copy-year, were associated with more rapid decline of gait speed(Supplemental Table 1).......Median age was 50 years old, the majority (58.7%) had college education or higher, mean CD4+ cell count was > 500 cells/μL and most (69.5%) had a suppressed HIV-1 RNA."
Figure 1.Adjusted Predictions of Gait Speed Decline by Haplogroup J with 95% CIs
Due to effective antiretroviral therapy (ART), people living with HIV (PLWHIV) have substantially longer life expectancies than in the pre-ART era [1, 2], yethave higher rates of chronic comorbidities and greater risk of premature deaththan demographically similar adults without HIV [3, 4].Accelerated functional decline and higher prevalence of frailty among PLWHIV have been observed compared to HIV-uninfected controls[5-8].Gait speed is an independent measure of physical function and a component of the assessment of frailty, and has been shown to predict functional decline, hospitalization, disability and deaths among older adults[6, 9].
An accelerated rate of decline in gait speed has been noted in older PLWHIV, which could be attributed to multiple factors, including characteristics shared with the general population (reduced energy production[10], compromised energy consumption [10, 11], changes in body composition [12], etc.), as well as unique challenges from HIV chronic infection[13, 14].
Mitochondria-which actively engage in cell energy production [15]-are likely an important contributor to functional aging in PLWHIV.Mitochondrial DNA (mtDNA)is associated with energy production, apoptosis, and inflammation pathways in cells [16], andhas been linked to age-related physical function decline[15, 17],frailty and mortality[18].Conversely, mitochondrial function among PLWHIV could be damaged by HIV chronic infection [14] and long-term usage of ART [13], which trigger proinflammatory responses that could lead to impaired physical function. It is possible that mtDNA genetic variation interact with multiple mechanisms and confer additional susceptibility to certain individuals.
Mitochondrial DNA haplogroups represent major branch points on the mitochondrial phylogenetic tree, and have been broadly used in studying human evolution and discovering genes involved in complex disease development [19]. Among the HIV-infected (HIV+) population, mtDNA haplogroups have been linked to progression to acquired immunodeficiency syndrome (AIDS) and mortality [20], as well as ART-associated peripheral neuropathy [21], but their association with physical function in PLWHIV has not been investigated. This study aimed to evaluate the association of common European mtDNA haplogroups with gait speed in PLWHIV to better understand the role of mitochondrial genetic background in aging-related declines in physical function.
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Accepted Manuscript
The Role of Mitochondrial DNA Variation in Age-Related Decline in Gait Speed Among Older Men Living with HIV
22 February 2018 -Clinical Infectious Diseases -Jing Sun1, Todd T. Brown1,2, David C. Samuels3, Todd Hulgan4, Gypsyamber D'Souza1, Beth D. Jamieson5, Kristine M. Erlandson8, Jeremy Martinson6, Frank J. Palella Jr.7, Joseph B. Margolick 1, Gregory D. Kirk1,2, Jennifer A. Schrack1,9
Abstract
Background
Age-related gait speed decline is accelerated in men with HIV. Mitochondrial genetic variation is associated with frailty and mortality in the general population, and may provide insight into mechanisms of functional decline in people aging with HIV.
Material & Methods
Gait speed was assessed semi-annually in the Multicenter AIDS Cohort Study (MACS). Mitochondrial DNA (mtDNA) haplogroups were extracted from genome-wide genotyping data, classifying men ≥ 50 years into 5 groups: mtDNA haplogroup H, J, T, Uk, and other. Differences in gait speed by haplogroups were assessed as: 1) rate of gait speed decline per year; 2) probability of slow gait speed (<1.0 m/s); and 3) hazard of slow gait using multivariable linear mixed-effects models, mixed-effects logistic regression models, and the Andersen-Gill Model, controlling for HCV infection, previous AIDS diagnosis, thymidine analogues exposure, education, body composition, smoking, and peripheral neuropathy. Age was further controlled for in the mixed-effects logistic regression models.
we only included HIV+ men in the current study. Furthermore, we restricted this analysis to men aged 50 or older, because a previous MACS study demonstrated an accelerated rate of gait speed decline after age 50 among HIV+ participants [6].
Results
455 HIV+ white men age ≥ 50 contributed 3,283 person-years of follow-up. Among them, 70% have achieved HIV viral suppression. In fully adjusted models, individuals with haplogroup J had more rapid decline in gait speed (adjusted slopes: 0.018 m/s/year vs. 0.011 m/s/year, pinteraction = 0.012), and increased risk of developing slow gait (adjusted OR: 2.97, 95% CI: 1.24-7.08) compared to those with other haplogroups.
Consistent with our previous study performed in MACS [6], HIV viral suppression did not have a significant effect on gait speed. However,having ever been diagnosed with AIDS, higher viremia copy-year, were associated with more rapid decline of gait speed(Supplemental Table 1)
Conclusions
Among older, HIV-infected men, mtDNA haplogroup J was an independent risk factor for more rapid age-related gait speed decline.
Figure 1. Adjusted Predictions of Gait Speed Decline by Haplogroup J with 95% CIs
BACKGROUND
Due to effective antiretroviral therapy (ART), people living with HIV (PLWHIV) have substantially longer life expectancies than in the pre-ART era [1, 2], yet have higher rates of chronic comorbidities and greater risk of premature death than demographically similar adults without HIV [3, 4]. Accelerated functional decline and higher prevalence of frailty among PLWHIV have been observed compared to HIV-uninfected controls [5-8]. Gait speed is an independent measure of physical function and a component of the assessment of frailty, and has been shown to predict functional decline, hospitalization, disability and deaths among older adults [6, 9].
An accelerated rate of decline in gait speed has been noted in older PLWHIV, which could be attributed to multiple factors, including characteristics shared with the general population (reduced energy production[10], compromised energy consumption [10, 11], changes in body composition [12], etc.), as well as unique challenges from HIV chronic infection [13, 14].
Mitochondria-which actively engage in cell energy production [15]-are likely an important contributor to functional aging in PLWHIV. Mitochondrial DNA (mtDNA) is associated with energy production, apoptosis, and inflammation pathways in cells [16], and has been linked to age-related physical function decline [15, 17], frailty and mortality [18]. Conversely, mitochondrial function among PLWHIV could be damaged by HIV chronic infection [14] and long-term usage of ART [13], which trigger proinflammatory responses that could lead to impaired physical function. It is possible that mtDNA genetic variation interact with multiple mechanisms and confer additional susceptibility to certain individuals.
Mitochondrial DNA haplogroups represent major branch points on the mitochondrial phylogenetic tree, and have been broadly used in studying human evolution and discovering genes involved in complex disease development [19]. Among the HIV-infected (HIV+) population, mtDNA haplogroups have been linked to progression to acquired immunodeficiency syndrome (AIDS) and mortality [20], as well as ART-associated peripheral neuropathy [21], but their association with physical function in PLWHIV has not been investigated. This study aimed to evaluate the association of common European mtDNA haplogroups with gait speed in PLWHIV to better understand the role of mitochondrial genetic background in aging-related declines in physical function.
Study Population
We used data from the Multicenter AIDS Cohort Study (MACS), a long-standing prospective community-based cohort that recruited men with and without HIV who have sex with men at four study sites (Baltimore/Washington DC, Chicago, Pittsburgh, and Los Angeles) starting in 1984. Institutional review boards at each study location approved the study protocol and each participant provided informed written consent. Descriptions of the study design, enrollment, and data collection can be found in previous publications [6, 22]. Briefly, participants were enrolled during three enrollmentperiods from 1984-5, 1987-91, and 2001-03, and attend routine semi-annual visits for standardized interviews, laboratory tests, and physical examinations. For purposes of this analysis, subjects were restricted to non-Hispanic white males, because the greatest proportion of MACS participants available for analysis were of non-Hispanic white race/ethnicity. We only included subjects who had two or more visits with physical function measurement and had genetic data available. No mtDNA haplogroup information was available for HIV- men at the time of analysis, thus we only included HIV+ men in the current study. Furthermore, we restricted this analysis to men aged 50 or older, because a previous MACS study demonstrated an accelerated rate of gait speed decline after age 50 among HIV+ participants [6].
Gait Speed
Gait speed was assessed semi-annually in meters per second (m/s) over a 4-meter course, using standard clinical procedures [23]. Participants were asked to walk at their "normal, comfortable pace." Timing was initiated with a command of "Go" and stopped after the first foot-fall over the finish line. Two measurements were conducted, with the faster measurement [24] used for analysis. A measurement of < 1 m/s was defined as clinically slow gait speed [23, 25]. Gait speeds over 1.7 m/s were recorded as missing (52 visits out of total of 4,031) in the analysis due to potential measurement error, as 1.7 m/s may be considered a transitional speed between walking and running [26, 27].
RESULTS
Baseline Characteristics
The study sample included 455 HIV+, self-reported non-Hispanic white men aged 50 and older who had > 2 study visits between October 1st, 2007 and September 30th, 2016. They contributed a total of 3,283 person-years of follow-up to the analysis (median follow-up: 21 person-years, IQR: 15-23). Table 1 demonstrates characteristicsof participants at baseline (first visit after October 1st, 2007 when participants were over age 50) by mtDNA haplogroups. Median age was 50 years old, the majority (58.7%) had college education or higher, mean CD4+ cell count was > 500 cells/μL and most (69.5%) had a suppressed HIV-1 RNA.
As presented in Table 1, H was the most prevalent haplogroup (41%), followed by Uk, T, and J. Baseline demographic and behavioral characteristics were similar by haplogroup. Mean gait speed at baseline visit was 1.15 m/s overall, and was slightly slower for participants with haplogroup J (not statistically significant, p-value: 0.29).
Gait Speed Decline and mtDNA Haplogroups
In four random effects mixed linear models (Table 2), all haplogroups had significant declines in gait speed over time. However, the interaction between haplogroup and time was only significant in the model with haplogroup J, suggesting the rate of gait speed decline over time was only significantly different when comparing haplogroup J vs. non-J (p-value for interaction between time and haplogroup: 0.012). As reflected in the table and Figure 1, gait speed declined at a slope of 0.018 m/s/year among haplogroup J vs. 0.011 m/s/year in non-J, after controlling for covariates. Consistent with our previous study performed in MACS [6], HIV viral suppression did not have a significant effect on gait speed.
However, having ever been diagnosed with AIDS, higher viremia copy-year, were associated with more rapid decline of gait speed (Supplemental Table 1). To prevent bias estimation from dichotomizing exposure (haplogroup) in mixed effect linear regression models, we also constructed a mixed effect linear regression model that fitall haplogroups as a categorical variable, and assessed the trajectory of gait speed decline in each haplogroup as compared to haplogroup H (Supplemental Table 2). All estimations were similar to the results presented in Table 2.
Probability of Slow Gait Speed by Haplogroup J
Mixed effects logistic regression models were used to examine differences in the probability of developing clinically slow gait speed between haplogroup J and non-J. Compared to non-J haplogroups, having haplogroup J was associated with 2.97-fold (95% CI: 1.24-7.08) higher risk of developing slow gait speed, after controlling for covariates (Table 3). The hazard ratio of slow gait speed among group J vs. non-J from the Andersen-Gill model confirmed these findings (adjusted hazard ratio: 1.60, 95% CI: 1.04-2.47).
DISCUSSION
To our knowledge, this is the first study evaluating the contribution of mitochondrial genetics to physical function in PLWHIV. We found that although there was no difference in gait speed at age 50, gait speed declined significantly faster among participants with haplogroup J than among participants with other haplotypes. In other studies, a minimum clinically meaningful difference in gait speed has generally been taken to be between 0.05 – 0.10 m/s [33]. Studenski, et. al. conducted pooled analysis of 9 large cohorts and suggested that the hazard of deaths for older adults decreased by 12% (95% CI: 0.87-0.90) with each increase of 0.1 m/s in gait speed [9]. According to our results, men with haplogroup J, declining 0.006 m/s faster per year than men withother haplogroups, would reach a difference of 0.05-0.1 m/s after 8 to 16 years (i.e., as early as age 58). Also, participants in haplogroup J had 2.97-fold increased risk of having a study visit with slow gait speed (<1 m/s). Both faster decline in gait speed and higher probabilities of slow gait among haplogroup J were independent from participants' HIV disease state and exposure to thymidine analogues. These findings support the hypothesis that inherited mtDNA variation is associated with physical function decline among PLWHIV.
Previous studies linking mtDNA haplogrous and health outcomes have also noted issues common to haplogroup J. Haplogroup J is known to be associated with increased penetrance of Leber hereditary optic neuropathy (LHON) [34, 35], possibility due to mtDNA defects. Gomez-Durán et al. observed that, compared to haplogroup H, cytoplasmic hybrids from haplogroup J contain less mtDNA and RNA, synthesized a smaller amount of mtDNA-encoded polypeptides, and also displayed lower oxygen consumption, lower mitochondrial inner membrane potential, and lower total ATP levels [37], suggesting less efficient mitochondrial function. Lower energy production and reduced energy consumption is associated with faster physical function decline in the general population [10, 11]. In contrast, Suissa, et al. observed that individuals with haplogroup J had a 2-fold increase in mtDNA copy number compared to haplogroup H [38]. It is possible that such increase might be due to compensatory response to mitochondrial function damage. Further studies should investigate associations between mtDNA genetics and mitochondrial heteroplasmy to verify these findings.
Within the HIV+ population, haplogroups J and U5 have been observed to be more common among those who display accelerated progression to AIDS and death [20]. The study suggested that both haplogroups (J & U5) contained uncoupling SNPs and were associated with lower ATP production and ROS generation compared to other haplogroups (e.g. H3, H4, H5, and H6) that were more tightly coupled [20], suggesting mtDNA haplogroups could be linked to mitochondrial function variation and play a role in AIDS progression. Our findings suggest that even among men who have achieved HIV viral suppression, such variants as found among haplogroup J could be associated with physical function decline and predict worse functional outcome in PLWHIV.
Studies linking mtDNA variation and physical function decline in the general population have yielded inconsistent findings. One study examined mtDNA variation in frail and non-frail older adults, and suggested that the mt204 C allele, a site that could affect the efficiency of mtDNA replication [39], was associated with a 2-fold increased odds of frailty and decreased grip strength [18]. In contrast, another study found no associations between any tested mtDNA haplogroup and frailty in a very old adult population [40], but did find that haplogroup K (a subgroup of Uk) was associated with a lower hazard of death (HR: 0.52, 95% CI: 0.30-0.91). Although this study was conducted in a relatively large sample with validated measurements, frailty phenotypes were measured at a baseline age of 85+, which may exceed the age at which frailty manifests [41, 42]. None of these studies prospectively evaluated associations between mtDNA genome and the trajectory of physical function decline.
The current study has several limitations. First, no women were studied, and the haplogroups studied were European ancestry-specific. These factors limit the generalizability of our findings. Second, our sample size was relatively small, and the results could be biased by unmeasured confounders leading to false positive findings. We also could not study sub-haplogroups within J, which might have their own specific associations with the outcomes of interest. Further studies are therefore needed to validate our results. Third, very few study visits were captured among individuals with J haplogroup after the age of 67 (total of 17 observations from 3 unique individuals). Thus, our findings may not be representative of those older than 67. Fourth, we were only able to capture viral load since seroconversion among those who were not seroprevalent at study baseline (35.6%) in the viremia copy-year measurement. Thus, we likely underestimated the viremia copy-year for those infected with HIV before they participated in the study. Last, due to the demands of physically attending study visits, men who were lost to follow-up might be sicker, thus we could have understated rate of decline in gait speed with age among all haplogroups.
This study has several strengths. We were able to evaluate the rate and trajectory of gait speed based on validated repeated measurements controlling for HIV disease state and thymidine analogues exposure, and to quantify differential decline of gait speed in PLWHIV with four major European mtDNA haplogroups. Although focused on a HIV+ population, this study may also improve understanding of the impact of inherited mtDNA on functional aging in the general population. Lastly, the MACS cohort recruitedbehaviorally and sociodemographically similar individuals, which minimizes confounding and makes it ideal for the study of genetics.
CONCLUSIONS
Individuals with mitochondrial haplogroup J had more rapid gait speed decline compared to persons with other common European mitochondrial haplogroups. These findings suggest a potential pathway through mtDNA to understand the pathophysiology of accelerated function decline among PLWHIV, and may be used to predict risk of function decline in this group if validated prospectively. Investigation into relationships between mitochondrial genetic variation and changes in physical function could bring insights toward development of interventions including personalized long-term disease management strategies that promote healthy aging among PLWHIV.
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